Author + information
- Received January 23, 2018
- Accepted February 7, 2018
- Published online May 28, 2018.
- Kevin Damman, MD, PhDa,
- Mauro Gori, MDb,c,
- Brian Claggett, PhDb,
- Pardeep S. Jhund, MB, PhDd,
- Michele Senni, MDc,
- Martin P. Lefkowitz, MDe,
- Margaret F. Prescott, PhDe,
- Victor C. Shi, MDe,
- Jean L. Rouleau, MDf,
- Karl Swedberg, MD, PhDg,h,
- Michael R. Zile, MDi,
- Milton Packer, MDj,
- Akshay S. Desai, MD, MPHb,
- Scott D. Solomon, MDb and
- John J.V. McMurray, MDd,∗ ()
- aDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- bDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- cCardiovascular Department, Azienda Ospedaliera Papa Giovanni XXIII Hospital, Bergamo, Italy
- dBritish Heart Foundation (BHF) Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- eNovartis Pharmaceuticals, East Hanover, New Jersey
- fInstitut de Cardiologie de Montréal, Université de Montréal, Montreal, Canada
- gDepartment of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
- hNational Heart and Lung Institute, Imperial College London, London, United Kingdom
- iMedical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
- jBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- ↵∗Address for correspondence:
Prof. John. J.V. McMurray, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom.
Objectives The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction.
Background Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin–angiotensin system.
Methods In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR.
Results At screening, the eGFR was 70 ± 20 ml/min/1.73 m2 and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range [IQR]: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (−1.61 ml/min/1.73 m2/year; [95% confidence interval: −1.77 to −1.44 ml/min/1.73 m2/year] vs. −2.04 ml/min/1.73 m2/year [95% CI: −2.21 to −1.88 ml/min/1.73 m2/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38).
Conclusions Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.
The PARADIGM HF study was funded by Novartis. Dr. Claggert is a consultant for Gilead, AO Biome, and Boehringer Ingelheim. Dr. Jhund is a consultant for and has received speaker and advisory board fees from Novartis. Drs. Lefkowitz, Prescott, and Shi are employees of and own stock in Novartis Pharmaceuticals. Dr. Rouleau is a consultant for Novartis, Bayer, and AstraZeneca. Drs. Swedberg and Zile are consultants for Novartis. Dr. Packer is a consultant for Amgen, AstraZeneca, Bayer Boehringer Ingelheim, Cardiorentis, Saiichi Sankyo, Gilead, NovoNordisk, Novartis, Relypsa, Sanofi, Teva, Takeda, and ZS Pharma. Dr. Desai has received consulting fees and research support from Novartis. Dr. Solomon has received research grants from and is a consultant for Novartis. Dr. McMurray is an employee of Glasgow University, and Glasgow University has been paid by Novartis for his participation in a number of trials, including PARADIGM-HF and lectures, advisory boards, and other meetings related to PARADIGM-HF and sacubitril/valsartan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Drs. Damman and Gori contributed equally to this work and are joint first authors. Drs. Solomon and McMurray contributed equally to this work and are joint senior authors.
- Received January 23, 2018.
- Accepted February 7, 2018.
- 2018 The Authors